This invention relates to electrotransport devices for delivering a therapeutic agent (e.g., a drug), which devices have improved safety and reduced potential for abuse. In particular, the devices of this invention are intended to administer the agent to the body by electrotransport through the skin or mucosa.
The term “electrotransport” as used herein refers generally to the delivery of an agent (e.g., a drug) through a membrane, such as skin, mucous membrane, or nails. The delivery is induced or aided by application of an electrical potential. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of a human body by electrotransport delivery through the skin. A widely used electrotransport process, electromigration (also called iontophoresis), involves the electrically induced transport of charged ions. Another type of electrotransport, electro-osmosis, involves the flow of a liquid. The liquid contains the agent to be delivered, under the influence of an electric field. Still another type of electrotransport process, electroporation, involves the formation of transiently-existing pores in a biological membrane by the application of an electric field. An agent can be delivered through the pores either passively (i.e., without electrical assistance) or actively (i.e., under the influence of an electric potential). However, in any given electrotransport process, more than one of these processes may be occurring simultaneously to a certain extent. Accordingly, the term “electrotransport”, as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture thereof, regardless of the specific mechanism or mechanisms by which the agent actually is transported.
Electrotransport devices use at least two electrodes that are in electrical contact with some portion of the skin, nails, mucous membrane, or other surface of the body. One electrode, commonly called the “donor” or “active” electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically termed the “counter” or “return” electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, i.e., a cation, then the anode is the active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if an agent is negatively charged, i.e., an anion, the cathode is the donor electrode. Additionally, both the anode and cathode may be considered donor electrodes if both anionic and cationic agent ions, or if uncharged dissolved agents, are to be delivered.
Furthermore, electrotransport delivery systems generally require at least one reservoir or source of the agent to be delivered to the body. Examples of such donor reservoirs include a pouch or cavity, a porous sponge or pad, and a hydrophilic polymer or a gel matrix. Such donor reservoirs are electrically connected to, and positioned between, the anode or cathode and the body surface, to provide a fixed or renewable source of one or more agents or drugs. Electrotransport devices also have an electrical power source such as one or more batteries. Typically, one pole of the power source is electrically connected to the donor electrode, while the opposite pole is electrically connected to the counter electrode. In addition, some electrotransport devices have an electrical controller that controls the current applied through the electrodes, thereby regulating the rate of agent delivery. Furthermore, passive flux control membranes, adhesives for maintaining device contact with a body surface, insulating members, and impermeable backing members are some other potential components of an electrotransport device.
All electrotransport agent delivery devices utilize an electrical circuit to 5 electrically connect the power source (e.g., a battery) and the electrodes. In very simple devices, such as those disclosed by Ariura et al. in U.S. Pat. No. 4,474,570, the “circuit” is merely an electrically conductive wire used to connect the battery to an electrode. Other devices use a variety of electrical components to control the amplitude, polarity, timing, waveform shape, etc. of the electric current supplied by the power source. See, for example, U.S. Pat. No. 5,047,007 issued to McNichols et al.
To date, commercial transdermal iontophoretic drug delivery devices (e.g., the Phoresor, sold by Iomed, Inc. of Salt Lake City, Utah; the Dupel Iontophoresis System sold by Empi, Inc. of St. Paul, Minn.; the Webster Sweat Inducer, model 3600, sold by Wescor, Inc. of Logan, Utah) have generally utilized a desk-top electrical power supply unit and a pair of skin contacting electrodes. The donor electrode contains a drug solution while the counter electrode contains a solution of a bio-compatible electrolyte salt. The “satellite” electrodes are connected to the electrical power supply unit by long (e.g., 1-2 meters) electrically conductive wires or cables. Examples of desk-top electrical power supply units which use “satellite” electrode assemblies are disclosed in Jacobsen et al. U.S. Pat. No. 4,141,359 (see FIGS. 3 and 4); LaPrade U.S. Pat. No. 5,006,108 (see FIG. 9), and Maurer et al. U.S. Pat. No. 5,254,081 (see FIGS. 1 and 2).
More recently, small self-contained electrotransport delivery devices adapted to be worn on the skin, sometimes unobtrusively under clothing, for extended periods of time have been proposed. The electrical components in such miniaturized iontophoretic drug delivery devices are also preferably miniaturized, and may be in the form of either integrated circuits (le, microchips) or small printed circuits. Electronic components, such as batteries, resistors, pulse generators, capacitors, etc., are electrically connected to form an electronic circuit that controls the amplitude, polarity, timing waveform shape, etc. of the electric current supplied by the power source. Such small self-contained electrotransport delivery devices are disclosed for example in Tapper U.S. Pat. No. 5,224,927; Haak et al. U.S. Pat. No. 5,203,768; Sibalis et al. U.S. Pat. No. 5,224,928; and Haynes et al. U.S. Pat. No. 5,246,418. One concern, particularly with small self-contained electrotransport delivery devices which are manufactured with the drug to be delivered already in them, is the potential loss in efficacy after a long period to of device storage. In an electrotransport device using batteries and other electronic components, all of the components have various shelf lives. If it is known, for example, that the batteries used to power these small delivery devices will gradually degrade, and the drug delivery rate may go off specification. It would be advantageous to have a means to limit the active life of the delivery device for a certain period of time (e.g., months) after device manufacture in order to prevent this potential loss in device efficacy.
Application of therapeutic drugs, whether by electrotransport or more traditional (e.g., oral) dosing, can sometimes cause unwanted reactions in certain patients. These reactions can take many forms, including change in heart rate, change in body temperature, sweating, shaking and the like. It would be advantageous to automatically and permanently disable an electrotransport drug delivery device upon encountering such “unwanted” reactions.
The potential for abuse by either oral or parenteral routes of narcotic and other psychoactive drugs is well known. For example, the potential for abuse of the synthetic narcotic drug fentanyl is so high that it has become a major cause of death for anesthesiologists and other hospital workers having access to the drug. In order to prevent abuse of these substances, it has been proposed to provide dosage forms which combine the abusable substance with an amount of an antagonist for the abusable substance sufficient to eliminate the “high” associated with abuse of the substance without eliminating the other therapeutic benefits for which the drugs are intended to be administered. See, for example, U.S. Pat. Nos. 4,457,933; 3,493,657; and 3,773,955, which are incorporated herein by reference.
Many abusable substances are capable of being administered to the body by direct application of the drug to the skin or mucosa, i.e., nasal, vaginal, oral, or rectal mucosa. See for example Gale et al. U.S. Pat. No. 4,588,580. They can also be delivered to the body by etectrotransport. See Theeuwes et al. U.S. Pat. No. 5,232,438 which is incorporated herein by reference. Electrotransport devices which are intended to deliver an abusable drug, such as a narcotic analgesic pain killing drug, could be subject to abuse.
Depending on the level of drug delivery that a particular patient needs in order to control pain, there may be a significant amount of drug left in a delivery device when it is discarded. When a conventional electrotransport device is discarded, it can be retrieved and reapplied (i.e., by an abuser) in order to deliver the remaining drug. It would clearly be desirable to have such devices available in a condition in which the abuse potential of the device is reduced without diminishing the intended therapeutic efficacy of the device or the abusable substance to be administered.